U.S. patent number 9,017,737 [Application Number 12/811,393] was granted by the patent office on 2015-04-28 for use of cannabinoids in combination with an anti-psychotic medicament.
This patent grant is currently assigned to GW Pharma Limited, Otsuka Pharmaceutical Co., Limited. The grantee listed for this patent is Geoffrey Guy, Tetsuro Kikuchi, Kenji Maeda, Philip Robson, Colin Stott. Invention is credited to Geoffrey Guy, Tetsuro Kikuchi, Kenji Maeda, Philip Robson, Colin Stott.
United States Patent |
9,017,737 |
Kikuchi , et al. |
April 28, 2015 |
Use of cannabinoids in combination with an anti-psychotic
medicament
Abstract
The present invention relates to the use of one or more
cannabinoids in combination with one or more anti-psychotic
medicaments for use in the prevention or treatment of psychosis and
psychotic disorders. Preferably the one or more cannabinoids are
taken from the group: cannabidiol (CBD); cannabidiolic acid (CBDA);
tetrahydrocannbidivarin (THCV); tetrahydrocannbidivarinin acid
(THCVA); cannabichromene (CBC); cannabichromenic acid (CBCA);
cannabigerol (CBG) and cannabigerolic acid (CBGA). Preferably the
anti-psychotic medication is an atypical anti-psychotic
medication.
Inventors: |
Kikuchi; Tetsuro (Osaka,
JP), Maeda; Kenji (Osaka, JP), Guy;
Geoffrey (Glanvilles Wootton, GB), Robson; Philip
(Wiltshire, GB), Stott; Colin (Wiltshire,
GB) |
Applicant: |
Name |
City |
State |
Country |
Type |
Kikuchi; Tetsuro
Maeda; Kenji
Guy; Geoffrey
Robson; Philip
Stott; Colin |
Osaka
Osaka
Glanvilles Wootton
Wiltshire
Wiltshire |
N/A
N/A
N/A
N/A
N/A |
JP
JP
GB
GB
GB |
|
|
Assignee: |
GW Pharma Limited (Salisbury,
GB)
Otsuka Pharmaceutical Co., Limited (Tokyo,
JP)
|
Family
ID: |
39144704 |
Appl.
No.: |
12/811,393 |
Filed: |
December 17, 2008 |
PCT
Filed: |
December 17, 2008 |
PCT No.: |
PCT/GB2008/004217 |
371(c)(1),(2),(4) Date: |
November 02, 2010 |
PCT
Pub. No.: |
WO2009/087351 |
PCT
Pub. Date: |
July 16, 2009 |
Prior Publication Data
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|
|
|
Document
Identifier |
Publication Date |
|
US 20110038958 A1 |
Feb 17, 2011 |
|
Foreign Application Priority Data
|
|
|
|
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Jan 4, 2008 [GB] |
|
|
0800390.7 |
|
Current U.S.
Class: |
424/725 |
Current CPC
Class: |
A61P
43/00 (20180101); A61K 36/185 (20130101); A61P
21/00 (20180101); A61K 31/35 (20130101); A61P
25/00 (20180101); A61P 25/24 (20180101); A61P
25/18 (20180101); A61P 27/02 (20180101); A61K
31/352 (20130101); A61P 25/22 (20180101); A61P
25/08 (20180101); A61K 45/06 (20130101); A61P
3/04 (20180101); A61K 31/05 (20130101); A61K
31/05 (20130101); A61K 2300/00 (20130101); A61K
31/35 (20130101); A61K 2300/00 (20130101); A61K
31/352 (20130101); A61K 2300/00 (20130101); A61K
36/185 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
36/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO-02/060423 |
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Aug 2002 |
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WO |
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WO-03/087037 |
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WO |
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WO-2004/060374 |
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WO |
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WO-2005/000830 |
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WO-2005/020992 |
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WO-2005/063761 |
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WO-2006/017892 |
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WO |
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WO-2006/054057 |
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May 2006 |
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WO |
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WO-2006/097605 |
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Sep 2006 |
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WO |
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WO 2007/067617 |
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Jun 2007 |
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WO |
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WO-2007/136571 |
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WO |
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WO 2007/144328 |
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WO |
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WO-2007/144628 |
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Dec 2007 |
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WO |
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WO-2008/133884 |
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Nov 2008 |
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WO |
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Other References
Zuardi et al, Cannabidiol monotherapy for treatment-resistant
Schizophrenia, Journal of psychopharmacology (Oxford, England),
(Sep. 2006) vol. 20, No. 5, pp. 683-686. cited by examiner .
Ozdemir, Aripiprazole Otsuka Pharmaceutical Co Ltd, Current Opinion
in Central & Peripheral Nervous System Investigational Drugs
(2000), 2(1), 105-111. cited by examiner .
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active metabolite dehydroaripiprazole in psychiatric patients.
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744-749. cited by examiner .
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1356-1370. cited by examiner .
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2011. cited by applicant .
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applicant .
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Fut. 2008;33(11):981-89. cited by applicant .
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vol. 4 (Part VII):169. Sanskrit. cited by applicant .
Khan et al., Ikseer Azam, vol. I. Fourth Edition. 1930:206.
Persian. cited by applicant .
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applicant .
Moreira et al., Cannabidiol inhibits the hyperlocomotion induced by
psychotomimetic drugs in mice. Eur J Pharmacol. Apr. 11,
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Russo et al., A tale of two cannabinoids: the therapeutic rationale
for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses.
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Sanskrit. cited by applicant .
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antipsychotic drug. Braz J Med Biol Res. Apr. 2006;39(4):421-9.
Epub Apr. 3, 2006. cited by applicant .
Cassano et al., Aripiprazole in the treatment of schizophrenia: a
consensus report produced by schizophrenia experts in Italy. Clin
Drug Investig. 2007;27(1):1-13. cited by applicant .
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applicant.
|
Primary Examiner: Mi; Qiuwen
Attorney, Agent or Firm: Wolf, Greenfield & Sacks,
P.C.
Claims
The invention claimed is:
1. A method for the treatment of psychosis or a psychotic disorder,
which comprises administering to a subject in need thereof a
therapeutically effective amount of THCV and/or CBD, in combination
with a sub-effective dose of an atypical anti-psychotic medicament,
wherein the THCV and/or CBD are administered separately,
sequentially or simultaneously to the atypical anti-psychotic
medicament so as to reduce or remove undesirable side effects of
the atypical anti-psychotic medicament and/or provide additional
anti-psychotic effects, wherein the atypical anti-psychotic
medicament is a dopamine-serotonin system stabilizer.
2. A method for the treatment of psychosis or a psychotic disorder
in a child or juvenile, which comprises administering to a subject
in need thereof a therapeutically effective amount of THCV and/or
CBD, in combination with a sub-effective dose of an atypical
anti-psychotic medicament, wherein the THCV and/or CBD are
administered separately, sequentially or simultaneously to the
atypical anti-psychotic medicament so as to reduce or remove
undesirable side effects of the atypical anti-psychotic medicament
and/or provide additional anti-psychotic effects, wherein the
atypical anti-psychotic medicament is a dopamine-serotonin system
stabilizer.
3. The method as claimed in claim 1, wherein the undesirable side
effects that are reduced or removed is obesity.
4. The method as claimed in claim 1, wherein the THCV and/or CBD
are present in the form of a cannabis plant extract, which
depending on the composition of the extract, has all or a
proportion of THC or THCA selectively removed.
5. The method as claimed in claim 1, wherein the THCV and/or CBD
are in the form of a botanical drug substance.
6. The method as claimed in claim 5, wherein the botanical drug
substance comprises all the naturally occurring phyto-cannabinoids
in the plant.
7. The method as claimed in claim 1, wherein the THCV and/or CBD in
a substantially pure form.
8. The method as claimed in claim 1, wherein the THCV and/or CBD
are in an isolated form.
9. The method as claimed in claim 1, wherein the THCV and/or CBD
are in a synthetic form.
10. The method as claimed in claim 1, wherein the THCV and/or CBD
are combined with the atypical anti-psychotic medicament and
formulated as a pharmaceutical composition further comprising one
or more pharmaceutically acceptable carriers, excipients or
diluents.
11. The method as claimed in claim 1, wherein the atypical
anti-psychotic medicament is selected from the group consisting of:
aripiprazole; a metabolite of aripiprazole; risperidone;
paliperidone; ziprasidone; olanzapine; quetiapine; clozapine;
sulpiride; amisulpride; iloperidone; cariprazine; and
asenapine.
12. The method as claimed in claim 11, wherein the atypical
anti-psychotic medicament is aripiprazole or a metabolite of
aripiprazole.
13. The method as claimed in claim 12, wherein the metabolite of
aripiprazole is dehydroaripiprazole, OPC-14857, DM-1458, DM-1451,
DM-1452, DM-1454 or DCPP.
14. The method as claimed in claim 1, wherein the psychosis or
psychotic disorder to be treated is selected from the group
consisting of: schizophrenia; schizophreniform disorder;
schizoaffective disorder; bipolar I disorder; bipolar II disorder;
major depressive disorder with psychotic feature; delusional
disorders; Shared Psychotic Disorder; Brief Psychotic disorder;
Psychotic disorder not otherwise specified; paranoid personality
disorder; schizoid personality disorder; and schizotypal
personality disorder.
15. The method as claimed in claim 14, wherein the schizophreniform
disorder is acute schizophrenic episode.
16. The method as claimed in claim 14, wherein the bipolar I
disorder is selected from the group consisting of: mania, manic
disorder, and manic-depressive psychosis.
17. The method as claimed in claim 14, wherein the major depressive
disorder with psychotic feature is psychotic depression.
18. The method as claimed in claim 14, wherein the delusional
disorder is paranoia.
19. The method as claimed in claim 14, wherein Shared Psychotic
Disorder is Shared paranoia disorder.
20. The method as claimed in claim 14, wherein the Brief Psychotic
disorder is Unspecified Reactive Psychosis.
21. The method as claimed in claim 1, wherein the undesirable side
effects that are reduced or removed are selected from the group
consisting of: catalepsy; and ptosis.
Description
RELATED APPLICATIONS
This application is a national stage filing under 35 U.S.C.
.sctn.371 of international application PCT/GB2008/004217, filed
Dec. 17, 2008, which was published under PCT Article 21(2) in
English.
BACKGROUND TO THE INVENTION
Psychosis and psychotic disorders are used to describe patients for
whom there is a loss of contact with reality.
Psychosis and psychotic disorders can result in a number of
symptoms including: hallucinations, where the patient senses things
that are not there; delusions, where the patient has beliefs that
are not based on reality; problems in clear thinking; and not
realising that there is anything wrong with them.
The following list illustrates a number of these disease states,
many of which are classified in the "Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, text revision"
(DSM-IV-TR) published by the American Psychiatric Association 2000:
schizophrenia; schizophreniform disorder (acute schizophrenic
episode); schizoaffective disorder; bipolar I disorder (mania,
manic disorder, manic-depressive psychosis); bipolar II disorder;
major depressive disorder with psychotic feature (psychotic
depression); delusional disorders (paranoia); shared psychotic
disorder (shared paranoia disorder); brief psychotic disorder
(other and unspecified reactive psychosis); psychotic disorder not
otherwise specified (unspecified psychosis); paranoid personality
disorder; schizoid personality disorder; and schizotypal
personality disorder.
Schizophrenia is a complex disease where the sufferer has
difficulty in understanding the difference between real and unreal
experiences. A patient suffering from schizophrenia also has
difficulty in logical thought and responding with normal emotions
in social and other situations.
Schizophrenia can take on different types: the catatonic type,
where the patient suffers motor disturbances, stupor, negativity,
rigidity, agitation, and inability to care for their personal needs
and a decreased sensitivity to painful stimuli; the paranoid type,
where the patient suffers with delusional thoughts of persecution
or of a grandiose nature; anxiety; anger; violence and
argumentativeness; and the disorganised type, where the patient is
incoherent and displays regressive behaviour, delusions,
hallucinations, inappropriate laughter, repetitive mannerisms and
social withdrawal.
Patients may also suffer with symptoms of one or more subtype or
may have had an abatement of the prominent symptoms but some
features such as hallucinations may remain.
Schizophreniform disorder (acute schizophrenic episode) is
characterized by the presence of some of the symptoms of
schizophrenia including: delusions, hallucinations, disorganised
speech, disorganised or catatonic behaviour, and negative symptoms.
The disorder--including its prodromal, active, and residual
phases--lasts longer than 1 month but less than 6 months.
Schizoaffective disorder symptoms can vary greatly from patient to
patient. Many patients suffer with problems with mood, daily
function or intrusive thoughts. Other symptoms can include
elevated, inflated or depressed mood; irritability and poor temper
control; changes in appetite, energy and sleep; hallucinations
(particularly auditory hallucinations); delusions of reference;
paranoia; deteriorating concern with hygiene and disorganised or
illogical speech.
Schizoaffective disorder features cycles of severe symptoms
followed by improvement.
Bipolar I disorder (mania, manic disorder, manic-depressive
psychosis) is characterised by mood swings that range from low
(feelings of intense depression and despair) to high (feelings of
elation, referred to as "mania") and can be mixed, for example a
depressed mood may be combined with restlessness and overactivity.
Often both depressive and manic episodes are experienced.
Bipolar II disorder is characterised by hypomanic episodes as well
as at least one major depressive episode. Hypomanic episodes do not
go to the extremes of mania (i.e. do not cause social or
occupational impairment, and are without psychotic features).
Bipolar II is much more difficult to diagnose, since the hypomanic
episodes may simply appear as a period of successful high
productivity and is reported less frequently than a distressing
depression. Psychosis can occur in manic and major depressive
episodes, but not in hypomania. For both disorders, there are a
number of specifiers that indicate the presentation and course of
the disorder, including "chronic", "rapid cycling", "catatonic" and
"melancholic".
Major depressive disorder with psychotic feature (psychotic
depression) is characterised in that a patient in addition to
suffering from depressive symptoms also suffers from hallucinations
or delusions. These patients often become paranoid and may believe
that their thoughts are not their own or that others can `hear`
their thoughts.
Delusional disorders (paranoia) are a form of psychosis where the
patient has long-lasting paranoid delusions which have no other
physical or medical cause. These delusions may also be accompanied
by auditory hallucinations.
Shared psychotic disorder (shared paranoia disorder) is a very rare
condition in which people close to a mentally ill person share his
or her false beliefs (delusions). As an example, a man with
schizophrenia may falsely believe that his children are trying to
murder him. His wife develops shared psychotic disorder and comes
to believe it as well. This disorder usually occurs in long-term
relationships and involves two people. However, it can also develop
among members of a group, such as within families. It affects women
more often than men.
Brief psychotic disorder (other and unspecified reactive psychosis)
is characterised by patients who experience an acute psychotic
episode lasting longer than one day but less than one month and
that may or may not immediately follow an important life stress or
a pregnancy (with postpartum onset). This illness usually comes as
a surprise as there is no forewarning that the person is likely to
break down, although this disorder is more common in people with a
pre-existing personality disorder.
Paranoid personality disorder is characterised by an exaggeration
of the cognitive modules for sensitivity to rejection,
resentfulness, distrust, as well as the inclination to distort
experienced events. Neutral and friendly actions of others are
often misinterpreted as being hostile or contemptuous. Unfounded
suspicions regarding the sexual loyalty of partners and loyalty in
general as well as the belief that one's rights are not being
recognized is stubbornly and argumentatively insisted upon. Such
individuals can possess an excessive self-assurance and a tendency
toward an exaggerated self-reference. Pathological jealousy,
instinctive aggressive counter-attack, the need to control others,
and the gathering of trivial or circumstantial "evidence" to
support their jealous beliefs also features.
Schizoid personality disorder (SPD) is characterised by a lack of
interest in social relationships, a tendency towards a solitary
lifestyle, secretiveness, and emotional coldness. SPD is reasonably
rare compared with other personality disorders, its prevalence is
estimated at less than 1% of the general population.
Schizotypal personality disorder, is characterized by a need for
social isolation, odd behaviour and thinking, and often
unconventional beliefs such as being convinced of having
extra-sensory abilities.
Psychosis and psychotic disorders are commonly treated with a class
of medication known as atypical anti-psychotics.
Atypical anti-psychotics are also known as second or third
generation anti-psychotics of which some are approved by the FDA
for use in the treatment of psychotic disorders including:
schizophrenia; bipolar disorder; mania and other indications.
Atypical anti-psychotics are a heterogeneous group of otherwise
unrelated drugs which are grouped as such due to the fact that they
work in a different manner to other typical anti-psychotics. Many,
but not all atypical anti-psychotics work by acting upon the
serotonin and dopamine receptor systems in the brain.
Examples of atypical anti-psychotic medicaments include but are not
limited to: aripiprazole; risperidone; paliperidone; ziprasidone;
olanzapine; quetiapine; clozapine; sulpiride; amisulpride;
iloperidone; cariprazine; asenapine.
Aripiprazole is a third generation antipsychotic. Aripiprazole has
activity as an agonist at the serotonin receptors and dopamine
receptors, and acts as an agonist or partial agonist at the
serotonin 5-HT1A receptor and as an agonist or partial agonist at
the dopamine D.sub.2 receptor. Aripiprazole is a dopamine-serotonin
system stabilizer.
Anti-psychotic medication is rarely used in children, although
recently both risperidone and aripiprazole have received FDA
approval for their use in the treatment of schizophrenia and mania
or mixed episodes of bipolar disorder in children and
adolescents.
The atypical anti-psychotics class of medicaments are most often
favoured by physicians in the treatment of psychotic disorders such
as schizophrenia, and their use is slowly replacing the use of
typical anti-psychotics such as fluphenazine, haloperidol and
chlorpromazine.
One characteristic of atypical anti-psychotics is the decreased
propensity of these medicaments to cause extrapyramidal side
effects in the absence of prolactin elevation.
The side-effects that have been reported for the class of
medicaments known as atypical anti-psychotics vary from drug to
drug.
The medicaments olanzapine and risperidone have been
contra-indicated in elderly patients with dementia due to an
increased risk of stroke.
It is also known that atypical anti-psychotics can cause abnormal
shifts in sleep patterns and as such result in extreme tiredness
and weakness.
Other side effects include tardive dyskinsia (involuntary jerking
and facial grimacing), and dystonia (involuntary muscle
contractions). In addition some atypical anti-psychotics may cause
serious metabolic disorders, similar to those caused by the typical
anti-psychotics.
Such metabolic disorders include hyperglycemia and diabetes.
There are also many reports that anti-psychotic drugs lead to a
host of side-effects related to the metabolism.
For example, weight gain, insulin resistance, type 1 and 2
diabetes, hyperlipidemia, hyperprolactinemia, and cardiovascular
disease are amongst the metabolically related side-effects that
patients taking anti-psychotic medication report.
Clearly there is a significant requirement for an efficacious
treatment that is able to prevent or treat psychosis or psychotic
disorders without resulting in side-effects. In particular the
reduction in the incidence of metabolically related side-effects is
of great importance as these diseases and conditions can be so
disabling that the patient may stop taking their medication in
order to alleviate the side-effects.
There are a number of documents which focus on the use of CB1
antagonists in combination with antipsychotics for this
purpose.
WO2006/097605 and US 2008/0015186 describe the use of a
pyrazole-based cannabinoid receptor (CB1) antagonist, specifically
rimonabant, with antipsychotics such as, risperidone, to counter
the weight problems, obesity and metabolic disorders associated
with the use of such antipsychotics. In other words both drugs
independently perform their natural function.
WO2007/136571 relates to the use of CB1 antagonists and inverse
agonists in combination with antipsychotic agents.
WO 03/087037 discloses a treatment for mania comprising using a CB1
receptor modulator in combination with an antipsychotic agent.
US2007/0105914 teaches using CB1 receptor modulators in combination
with conventional antipsychotic drugs.
WO2005/063761 describes Azabicyclic heterocycles as cannabinoid
receptor modulators and suggests these compounds may be used in
combination with antipsychotic agents.
WO2005/020992 suggests countering the problem of weight gain
associated with many atypical antipsychotics by co-administering a
CB1 antagonist.
By and large these documents are speculative in nature suggesting
combinations of many different synthetic compounds with little or
no support. No one has however specifically investigated using
phyto-cannabinoids in combination with antipsychotics.
WO 2006/054057 discloses using the phyto-cannabinoid THCV in the
treatment of disease indications associated with the CB1
cannabinoid receptor based on the surprising discovery it is a
neutral CB1 antagonist (in contrast to THC which although
structurally similar is a CB1 agonist). It suggests using it for
the treatment of e.g. obesity and schizophrenia but makes no
suggestion of using it in combination with other drugs.
Cannabinoids are a group of chemicals known to activate cannabinoid
receptors in cells. These chemicals, which are found in cannabis
plants, are also produced endogenously in humans and other animals.
These are termed endocannabinoids. Synthetic cannabinoids are
chemicals with similar structures to plant cannabinoids or
endocannabinoids and it is, of course, possible to also make
synthetic versions of these plant cannabinoids or
endocannabinoids.
Cannabinoids possess the characteristics of being cyclic molecules
exhibiting particular properties such as the ability to easily
cross the blood-brain barrier, weak toxicity and few side
effects.
Plant cannabinoids or phyto-cannabinoids can also be isolated such
that they are "essentially pure" compounds. These isolated
cannabinoids are essentially free of the other naturally occurring
compounds, such as, other minor cannabinoids and molecules such as
terpenes.
Essentially pure compounds have a degree of purity up to at least
95% by total weight. Some essentially pure cannabinoids (whether
synthetic or isolated) have been suggested to be neuroprotective
agents, either by direct antagonism of the NMDA receptor or by
reducing the influx of calcium ions into the cell by another means
such as binding with cannabinoid receptors.
However, current thinking is such that it is generally believed
that cannabis, and by implication the phyto-cannabinoids, may be
responsible for users (particularly juveniles) developing
psychological illnesses. This is mainly due to the condition known
as cannabis psychosis. Cannabis use has been linked to psychosis by
several peer-reviewed studies. A 1987 Swedish study claimed a link
between cannabis use and schizophrenia. More recently, the Dunedin
Multidisciplinary Health and Development Study published research
showing an increased risk of psychosis for cannabis users with a
certain genetic predisposition, held by 25% of the population. In
2007, a study published in The Lancet and a poll of mental health
experts showed that a growing number of medical health
practitioners are convinced that cannabis use increases
susceptibility to mental illness, accounting for 14% of the United
Kingdom's psychosis cases.
It is likely that the link between cannabis use and psychosis is as
a consequence of the high concentration of the psychoactive
cannabinoid tetrahydrocannabinol (THC) that is found in most
recreational cannabis.
Despite the strong prejudice against cannabis, the applicant
believes there is significant credible evidence supporting the use
of certain phyto cannabinoid based medicines in combination with
atypical anti-psychotic drugs. The rationale for this is outlined
below.
Some plant cannabinoids have been found to be effective agents in
the treatment of psychosis or psychotic disorders. For example, the
applicant has demonstrated in their co-pending patent application
WO 2005/000830 the use of cannabichromene (CBC) type compounds and
derivatives in the treatment of mood disorders. The mood disorders
to be treated are taken from the group: morbid or clinical
depression; unipolar mood disorder; bipolar mood disorder;
syndromal depression; panic disorder and anxiety.
Additionally the applicant has also described in their co-pending
application PCT/GB2007/0020216 the use of cannabigerol (CBG) type
compounds (including cannabigerol propyl analogue (CBGV)) and their
derivatives in the treatment of mood disorders. Similarly the mood
disorders to be treated are taken from the group: morbid or
clinical depression; unipolar mood disorder; bipolar mood disorder;
syndromal depression; panic disorder and anxiety.
In addition to the evidence supporting the use of specific
cannabinoids in the treatment of psychotic disorders, there is also
credible evidence supporting the use of specific cannabinoids to
treat a number of diseases or conditions such as for example
stroke, diabetes and other metabolic disorders, where use of the
atypical anti-psychotic medicaments are contra-indicated.
Thus whilst single cannabinoids might be used in combination with
atypical anti-psychotics a preferred approach may be to use
combinations of cannabinoids which may or may not be present as a
cannabis plant extract. Depending on the extract selected it may
desirable to selectively remove all or a proportion of THC or THCA
from the extract.
SUMMARY OF INVENTION
According to the first aspect of the present invention there is
provided the use of one or more phyto-cannabinoids with one or more
anti-psychotic medicaments in the manufacture of a pharmaceutical
formulation for use in the prevention or treatment of psychosis or
a psychotic disorder, wherein the one or more phyto-cannabinoids
are administered separately, sequentially or simultaneously to the
one or more anti-psychotic medicaments.
Preferably the one or more phyto-cannabinoids are taken from the
group: cannabidiol (CBD); cannabidiolic acid (CBDA);
tetrahydrocannbidivarin (THCV); tetrahydrocannbidivarinin acid
(THCVA); cannabichromene (CBC); cannabichromenic acid (CBCA);
cannabigerol (CBG) and cannabigerolic acid (CBGA).
Preferably the plurality of phyto-cannabinoids are present in the
form of a cannabis plant extract, which depending on the
composition of the extract, may have all or a proportion of THC or
THCA selectively removed.
More preferably the cannabinoid extract from at least one cannabis
plant is a botanical drug substance.
Preferably the cannabinoid extract from at least one cannabis plant
is produced by extraction with supercritical or subcritical
CO.sub.2.
Alternatively the cannabinoid extract from at least one cannabis
plant is produced by contacting plant material with a heated gas at
a temperature which is greater than 100.degree. C., sufficient to
volatilise one or more of the cannabinoids in the plant material to
form a vapour, and condensing the vapour to form an extract.
Alternatively the one or more cannabinoids, including
phyto-cannabinoids, may be present in a substantially pure or
isolated form.
A "substantially pure" preparation of cannabinoid is defined as a
preparation having a chromatographic purity (of the desired
cannabinoid) of greater than 90%, more preferably greater than 95%,
more preferably greater than 96%, more preferably greater than 97%,
more preferably greater than 98%, more preferably greater than 99%
and most preferably greater than 99.5%, as determined by area
normalisation of an HPLC profile.
Preferably the substantially pure cannabinoid used in the invention
is substantially free of any other naturally occurring or synthetic
cannabinoids, including cannabinoids that occur naturally in
cannabis plants. In this context "substantially free" can be taken
to mean that no cannabinoids other than the target cannabinoid are
detectable by HPLC.
Substantially pure cannabinoids can be prepared from a botanical
drug substance. A technique has been established by the applicant
and is described in their granted United Kingdom patent,
GB2393721.
In another aspect of the present invention the cannabinoid is in a
synthetic form.
References to cannabinoids, particularly with regard to therapeutic
use, will be understood to also encompass pharmaceutically
acceptable salts of the cannabinoid. The term "pharmaceutically
acceptable salts" refers to salts or esters prepared from
pharmaceutically acceptable non-toxic bases or acids, including
inorganic bases or acids and organic bases or acids, as would be
well known to persons skilled in the art. Many suitable inorganic
and organic bases are known in the art.
The scope of the invention also extends to derivatives of
cannabinoids that retain the desired activity. Derivatives that
retain substantially the same activity as the starting material, or
more preferably exhibit improved activity, may be produced
according to standard principles of medicinal chemistry, which are
well known in the art. Such derivatives may exhibit a lesser degree
of activity than the starting material, so long as they retain
sufficient activity to be therapeutically effective. Derivatives
may exhibit improvements in other properties that are desirable in
pharmaceutically active agents such as, for example, improved
solubility, reduced toxicity, enhanced uptake, etc.
Preferably, the cannabinoid combined with the anti-psychotic
medicament is formulated as a pharmaceutical composition further
comprising one or more pharmaceutically acceptable carriers,
excipients or diluents.
The invention also encompasses pharmaceutical compositions
comprising cannabinoids, or pharmaceutically acceptable salts or
derivatives thereof in combination with anti-psychotic medicaments,
formulated into pharmaceutical dosage forms, together with suitable
pharmaceutically acceptable carriers, such as diluents, fillers,
salts, buffers, stabilizers, solubilizers, etc. The dosage form may
contain other pharmaceutically acceptable excipients for modifying
conditions such as pH, osmolarity, taste, viscosity, sterility,
lipophilicity, solubility etc. The choice of diluents, carriers or
excipients will depend on the desired dosage form, which may in
turn be dependent on the intended route of administration to a
patient.
Suitable dosage forms include, but are not limited to, solid dosage
forms, for example tablets, capsules, powders, dispersible
granules, cachets and suppositories, including sustained release
and delayed release formulations. Powders and tablets will
generally comprise from about 5% to about 70% active ingredient.
Suitable solid carriers and excipients are generally known in the
art and include, e.g. magnesium carbonate, magnesium stearate,
talc, sugar, lactose, etc. Tablets, powders, cachets and capsules
are all suitable dosage forms for oral administration.
Liquid dosage forms include solutions, suspensions and emulsions.
Liquid form preparations may be administered by intravenous,
intracerebral, intraperitoneal, parenteral or intramuscular
injection or infusion. Sterile injectable formulations may comprise
a sterile solution or suspension of the active agent in a
non-toxic, pharmaceutically acceptable diluent or solvent. Liquid
dosage forms also include solutions or sprays for intranasal,
buccal or sublingual administration. Aerosol preparations suitable
for inhalation may include solutions and solids in powder form,
which may be combined with a pharmaceutically acceptable carrier,
such as an inert compressed gas.
Also encompassed are dosage forms for transdermal administration,
including creams, lotions, aerosols and/or emulsions. These dosage
forms may be included in transdermal patches of the matrix or
reservoir type, which are generally known in the art.
Pharmaceutical preparations may be conveniently prepared in unit
dosage form, according to standard procedures of pharmaceutical
formulation. The quantity of active compound per unit dose may be
varied according to the nature of the active compound and the
intended dosage regime. Generally this will be within the range of
from 0.1 mg to 5000 mg per unit dose.
Preferably the one or more anti-psychotic medicaments are atypical
anti-psychotic medicaments.
More preferably the atypical anti-psychotic medicament is taken
from the group: aripiprazole; risperidone; paliperidone;
ziprasidone; olanzapine; quetiapine; clozapine; sulpiride;
amisulpride; iloperidone; cariprazine; asenapine.
More preferably the atypical anti-psychotic medicament is
aripiprazole, which may be in a form of its pharmaceutically
acceptable salt, suitable solvates (hydrate, ethanolate, etc),
metabolites, anhydrous crystals, etc, shown in WO2004/060374.
Aripiprazole, also called
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quin-
-olinone, is a carbostyril compound and is useful for treating
schizophrenia (EP 0 367 141, U.S. Pat. No. 5,006,528). Aripiprazole
is also known as
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril-
-, Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole
possesses 5-HT1A receptor agonist activity, and is known as useful
compound for treating types of depression and refractory
depressions, such as endogeneous depression, major depression,
melancholia and the like (WO 02/060423, U.S. Patent Application
2002/0173513A1). Aripiprazole has activity as an agonist at the
serotonin receptors and dopamine receptors, and acts as an agonist
or partial agonist at the serotonin 5-HT1A receptor and as an
agonist or partial agonist at the dopamine D.sub.2 receptor.
Aripiprazole is a dopamine-serotonin system stabilizer. Metabolites
of aripiprazole are included within the scope of the present
invention. One such metabolite of aripiprazole is called
dehydroaripiprazole. Preferred metabolites of aripiprazole included
within the present invention are indicated by the following
designations: OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and
DCPP. Aripiprazole and aripiprazole metabolites to be used in the
present invention may be any of form, for example, free bases,
polymorphisms of every type of crystal, hydrate, salts (acid
addition salts, etc.) and the like. Among of these forms, anhydrous
aripiprazole crystals B is a preferred form. As to method for
preparing the anhydrous aripiprazole crystals B, for example it is
prepared by heating aripiprazole hydrate A, the details of which
are shown in WO2004/060374.
Dosage of the drug used in the present invention is decided by
considering the properties of each constituent drug to be combined,
the properties of the drug combination and the symptoms of the
patient.
Aripiprazole or a metabolite, such as dehydroaripiprazole, DM-1458,
DM-1451, DM-1452, DM-1454 or DCPP will generally be used in an
amount of about 0.1 to 100 mg/once a day (or about 0.05 to about 50
mg/twice a day), and more preferably in an amount of about 1 to 30
mg/once a day (or about 0.5 to about 15 mg/twice a day).
Generally, the weight ratio of the cannabinoids to the
anti-psychotic medicament is decided by considering the properties
of each constitute drug to be combined, the properties of drug
combination and the symptoms of the patient. Preferably the weight
ratio is in the range of about 1 part by weight of the cannabinoid
to about 0.01 to about 500 parts by weight of the anti-psychotic,
more preferably 1 part by weight of the cannabinoid to about 0.1 to
about 100 parts by weight of the anti-psychotic.
More preferably the cannabinoid is a phyto-cannabinoid which may be
present as a synthesised compound, an isolated compound or as an
extract containing one or more other phyto-cannabinoids and other
plant constituents in varying amounts. The extract may have had
individual cannabinoids, such as THC, selectively removed in whole
or part.
Examples of suitable phyto-cannabinoid extracts are illustrated in
Table 1 below:
The components of the THCV and CBD plant extracts used in the
following examples are described in Table 1 below.
TABLE-US-00001 TABLE 1 components of exemplary THCV and CBD plant
extracts THCV-rich extract CBD-rich extract (% w/w of (% w/w of
extract) extract) Primary/Secondary Cannabinoid: THC Content NMT
20% 2.0-6.5 CBD Content 57.0-72.0 THCV Content NLT 50% -- Other
Cannabinoids: Cannabigerol 0.8-6.5 Cannabichromene 3.0-6.5
Tetrahydrocannabinolic -- acid Cannabidivarin 1.0-2.0 Cannabidiolic
acid <2.0 Terpenes: Monoterpenes 0.4 Di/tri-terpenes 0.4
Sesquiterpenes 2.0
Preferably the psychosis or psychotic disorder to be treated is
taken from the group: schizophrenia; schizophreniform disorder
(acute schizophrenic episode); schizoaffective disorder; bipolar I
disorder (mania, manic disorder, manic-depressive psychosis);
bipolar II disorder; major depressive disorder with psychotic
feature (psychotic depression); delusional disorders (paranoia);
shared psychotic disorder (shared paranoia disorder); brief
psychotic disorder (other and unspecified reactive psychosis);
psychotic disorder not otherwise specified (unspecified psychosis);
paranoid personality disorder; schizoid personality disorder; and
schizotypal personality disorder.
According to a second aspect of the present invention there is
provided the use of one or more phyto-cannabinoids with one or more
anti-psychotic medicaments in the manufacture of a pharmaceutical
formulation for use in the prevention or treatment of psychosis or
a psychotic disorder in children and juveniles, wherein the one or
more phyto-cannabinoids are administered separately, sequentially
or simultaneously to the one or more anti-psychotic
medicaments.
According to a third aspect of the present invention there is
provided a method for the treatment or prevention of psychosis or a
psychotic disorder, which comprises administering to a subject in
need thereof a therapeutically effective amount of one or more
phyto-cannabinoids in combination with one or more anti-psychotic
medicaments.
The subject may be an adult, child or juvenile.
According to a forth aspect of the present invention there is
provided a pharmaceutical formulation for use in the prevention or
treatment of psychosis or a psychotic disorder, which comprises one
or more phyto-cannabinoids and one or more anti-psychotic
medicaments, for administration separately, sequentially or
simultaneously.
Certain aspects of this invention are further described, with
reference to the following examples and data in which:
FIG. 1 illustrates the dosing regime in a conditioned avoidance
experiment using the cannabinoid CBD with the atypical
antipsychotic Aripiprazole APZ;
FIG. 2 illustrates the dosing regime in a conditioned avoidance
experiment using the cannabinoid THCV with the atypical
antipsychotic Aripiprazole;
FIG. 3 illustrates the effects of THCV, APZ and the combination
THCV and APZ at individually sub-effective doses;
FIG. 4 illustrates the effects of THCV, APZ and the combination
THCV and APZ at individually effective doses;
FIG. 5 illustrates the dosing regime used in a Catalepsy and Ptosis
study with CBD and THCV respectively;
FIG. 6a illustrates the action of Aripiprazole alone;
FIG. 6b illustrates the combination effect with CBD;
FIG. 6c illustrates the combination effect with THCV;
FIG. 7 illustrates the combination effect of Aripiprazole and CBD
on Aripiprazole induced Ptosis; and
FIG. 8 illustrates the combination effect of Aripiprazole and THCV
on Aripiprazole induced Ptosis.
SPECIFIC DESCRIPTION
In addition to the data presented in WO 2005/000830 and
PCT/GB2007/0020216, which data indicates that certain cannabinoids
act as anti-psychotics per se, there is presented herein further
evidence supporting why the use of one or more cannabinoids in
combination with an atypical anti-psychotic medicament is likely to
be more beneficial than the atypical anti-psychotic alone.
Examples 1 and 2, describe the use of a combination of the
cannabinoids tetrahydrocannabivarin (THCV) and cannabidiol (CBD) to
in a dietary induced obese mouse model to demonstrate the metabolic
effects of the cannabinoids and by implication the potential
benefits in counteracting some common side effects resulting from
use of atypical anti-psychotics.
Example 3 describes how the cannabinoid CBD is a PPAR.gamma.
agonist, and provides further evidence of the potential benefits in
counteracting some common side effects resulting from use of
atypical anti-psychotics by demonstrating that PPAR.gamma. ligands
have beneficial effects in type 2 diabetes and the cardiovascular
system.
Examples 4 to 5 are results obtained from in vivo pharmacological
studies:
Example 4 is a conditioned avoidance response study which is an
animal model for efficacy and looked at combinations of
Aripiprazole with THCV;
Example 5 is a cataleptogenicity study which is an animal model for
extrapyramidal side effects and looked at combinations of
Aripiprazole with CBD (5a) and THCV (5b).
Example 1
An acute single dose study was undertaken where dietary-induced
obese mice were dosed with either: Pure THCV (0.3 mg/kg)+CBD BDS
(CBD at 0.3 mg/kg); or Pure THCV (3.0 mg/kg)+CBD BDS (CBD at 3.0
mg/kg).
Dietary-induced obese mice are a standard model used to evaluate
agents likely to affect metabolic symptoms including obesity, type
1 or 2 diabetes and dyslipidemia. CB.sub.1 antagonists are being
examined as potential anti-obesity agents and rimonabant has been
licensed. Rimonabant shows anti-obesity effects in man and rodent
models. Although in rodent models it reduces food intake over the
first few days, the long term anti-obesity effect seems to be more
related to energy expenditure increases, possibly mediated via
increased release of adiponectin from adipose tissue.
THCV and CBD are natural products with significant activity at the
CB.sub.1 receptor. The example described here was designed to
explore anti-obesity and the consequential metabolic effects by
measurement of food intake and body weight change after the single
dose of the combination of cannabinoids.
Animals were dosed just before lights out and food intake was
measured at 2 h, 4 h and 24 h.
Results:
There was no difference in effect after a single dose on the body
weight of the study animals dosed with the combination of THCV and
CBD in comparison to the control animals after the single dose
(data not shown).
However, there was a decrease in the amount of food consumed over
24 hours in the animals treated with the combination of THCV and
CBD as shown in Table 2 below.
TABLE-US-00002 TABLE 2 Food consumption Food consumption (g/animal)
2 hours 4 hours 24 hours Control 0.5 1.0 4.3 THCV + CBD (both 0.3
mg/kg) 0.5 0.8 3.8 THCV + CBD (both 3.0 mg/kg) 0.25 0.7 3.3
As can be seen from the results above the single dose of the
combined THCV and CBD resulted in a reduction of food intake within
4 hours of administration. This reduction was still observed at 24
hrs post dose. The reduction in food intake was more marked in the
higher dose group.
Example 2
A chronic dosing, 28-day study was undertaken where dietary-induced
obese mice were dosed daily at 09:00 by oral gavage with either:
Pure THCV (0.3 mg/kg)+CBD BDS (CBD at 0.3 mg/kg); or Pure THCV (3.0
mg/kg)+CBD BDS (CBD at 3.0 mg/kg).
Animals were acclimatised during Days 1-2 of the study and dosing
was started on Day 3.
Measurements were taken to provide data for the following: Food and
water intake (daily); Body weight (twice weekly); 24 h energy
expenditure (Days 3 and 10); Oral Glucose Tolerance Test (OGTT,
glucose load 3 g/kg) in 5 h-fasted mice (Days 7 and 21); Thermic
response to a mixed meal (Day 17) Body composition (% body fat) by
Dexascan in anaesthetised mice (Day 28) Nose-anus length
measurement (Day 28) Blood sample from fed mice for measurement of
glucose, lactate, insulin, triglycerides, cholesterol,
HDL-cholesterol (Day 28); Blood sample from fasted mice for
measurement of glucose, free fatty acids, insulin and adiponectin
(Day 30); and 2-3 h post-dosing drug levels & endocannabinoid
level (Day 30).
It is advantageous to know whether any anti-obesity effects are a
loss of fat mass (desirable) or a proportionate loss of fat and
lean tissue (undesirable). These data were achieved via a Dexascan
measurement and measurement of the plasma leptin concentration
which is known to correlate with adipose tissue mass.
Energy expenditure was measured by indirect calorimetry on two
occasions in order to see if there is either tolerance or an
induction process. In addition to the 24 h metabolic rate, the
thermic response to a mixed meal was determined. Studies on
rimonabant have shown an up-regulation of adiponectin mRNA in
adipose tissue. This cytokine is now viewed as an important
component of the energy balance control system. In addition
adiponectin knock-out mice are obese and insulin resistant and
administration of recombinant adiponectin to genetic and
dietary-induced obese mice reduces fat mass and improves insulin
action. Thus, adiponectin might be a mediator of the energy wasting
processes.
Loss of body fat and increase in energy expenditure both improve
insulin sensitivity. This was determined from glucose and insulin
concentrations in 5 h-fasted mice and through measurement of
glucose tolerance.
Potential effects on plasma lipids were also determined.
Results:
TABLE-US-00003 TABLE 3 Energy expenditure over 24 hours Energy
expenditure (kJ/h/animal) AUC Control 210 THCV + CBD (both 0.3
mg/kg) 290 THCV + CBD (both 3.0 mg/kg) 310
TABLE-US-00004 TABLE 4 Energy expenditure per Kg over 24 hours
Energy expenditure (kJ/h/Kg) AUC Control 4250 THCV + CBD (both 0.3
mg/kg) 5750 THCV + CBD (both 3.0 mg/kg) 6500
Both the low and the high dose combination of THCV+CBD increased
the energy expenditure of the animals 24 hours post dosing.
TABLE-US-00005 TABLE 5 Energy expenditure over 3 hours Energy
expenditure (kJ/h/animal) AUC Control 14.0 THCV + CBD (both 0.3
mg/kg) 21.5 THCV + CBD (both 3.0 mg/kg) 25.0
TABLE-US-00006 TABLE 6 Energy expenditure per Kg over 3 hours
Energy expenditure (kJ/h/Kg) AUC Control 400 THCV + CBD (both 0.3
mg/kg) 510 THCV + CBD (both 3.0 mg/kg) 500
Both the low and the high dose combination of THCV+CBD
significantly increased the energy expenditure 3 hours post
dosing.
TABLE-US-00007 TABLE 7 Bodyweight gain Body weight gain (g) Control
8.5 THCV + CBD (both 0.3 mg/kg) 9.5 THCV + CBD (both 3.0 mg/kg)
9.0
Neither the low or high dose of the combination of THCV+CBD reduced
the amount of body weight gain in comparison to the control
group.
TABLE-US-00008 TABLE 8 Food intake per animal Food intake
(g/animal) Control 3.9 THCV + CBD (both 0.3 mg/kg) 3.5 THCV + CBD
(both 3.0 mg/kg) 3.6
Cumulative food intake generally increased over the 28-day dosing
period in all groups. The lower dose combination of THCV+CBD
produced the smallest intake.
TABLE-US-00009 TABLE 9 Glucose tolerance test Glucose tolerance
([Blood Glucose]/ animal) Day 7 Day 23 Control 12 8 THCV + CBD
(both 0.3 mg/kg) 13 11 THCV + CBD (both 3.0 mg/kg) 18 16
TABLE-US-00010 TABLE 10 Glucose tolerance test (AUC) Glucose
tolerance (OGTT AUC 0-120) Day 7 Day 23 Control 2250 1950 THCV +
CBD (both 0.3 mg/kg) 2400 2200 THCV + CBD (both 3.0 mg/kg) 2600
2500
Neither combination of THCV+CBD improved the glucose tolerance of
the animals studied.
TABLE-US-00011 TABLE 11 Plasma insulin 30 min pre-dose Plasma
insulin ([Blood Insulin] pmol/L) Day 7 Day 23 Control 9000 13000
THCV + CBD (both 0.3 mg/kg) 7500 11000 THCV + CBD (both 3.0 mg/kg)
12500 8500
Plasma insulin levels were improved by the higher dose combination
of THCV+CBD.
TABLE-US-00012 TABLE 12 Fed glucose levels Glucose levels ([Blood
Glucose] mmol/L) Control 6.0 THCV + CBD (both 0.3 mg/kg) 10.0 THCV
+ CBD (both 3.0 mg/kg) 9.5
TABLE-US-00013 TABLE 13 Fasted glucose levels Glucose levels
([Blood Glucose] mmol/L) Control 6.0 THCV + CBD (both 0.3 mg/kg)
6.8 THCV + CBD (both 3.0 mg/kg) 7.0
The fed and fasted blood glucose concentrations were increased in
both study groups in comparison to the control.
TABLE-US-00014 TABLE 14 Total body fat Body fat (g) (%) Control 33
62.0 THCV + CBD (both 0.3 mg/kg) 33 61.5 THCV + CBD (both 3.0
mg/kg) 31 60.0
The amount of body fat in the animals treated with the combination
of THCV+CBD had a tendency for reduction particularly at the higher
dose. It should be noted that any effect may have been masked by an
increased food intake.
TABLE-US-00015 TABLE 15 Anus-nose length Lenth (mm) Control 92.3
THCV + CBD (both 0.3 mg/kg) 92.5 THCV + CBD (both 3.0 mg/kg)
91.7
TABLE-US-00016 TABLE 16 Triglyceride levels Triglyceride levels
([Blood Triglyceride] mmol/L) Control 0.42 THCV + CBD (both 0.3
mg/kg) 0.55 THCV + CBD (both 3.0 mg/kg) 0.62
The triglyceride level was slightly increased with both the low and
high dose THCV+CBD.
TABLE-US-00017 TABLE 17 Total cholesterol levels Cholesterol levels
([Blood cholesterol] mmol/L) Control 5.5 THCV + CBD (both 0.3
mg/kg) 7.2 THCV + CBD (both 3.0 mg/kg) 4.1
As can be seen above the concentration of total cholesterol in the
blood was vastly reduced by the higher dose combined THCV+CBD.
TABLE-US-00018 TABLE 18 HDL cholesterol levels HDL cholesterol
levels ([Blood HDL cholesterol] mmol/L) Control 2.00 THCV + CBD
(both 0.3 mg/kg) 3.25 THCV + CBD (both 3.0 mg/kg) 3.00
The table above demonstrates how the HDL cholesterol concentration
in the blood was dramatically increased by both the low and high
doses of the combination of THCV+CBD.
Conclusions
Pure THCV+CBD BDS reduces percentage body fat; Pure THCV+CBD BDS
significantly increases energy expenditure (low & high dose);
Pure THCV+CBD BDS produced a major reduction in total cholesterol
levels (high dose); Pure THCV+CBD BDS produced a major increase in
HDL cholesterol levels (low & high dose levels).
Example 3
The example described below investigated whether the cannabinoids,
cannabidiol (CBD) and tetrahydrocannabivarin (THCV), act via the
peroxisome proliferator-activated receptor gamma (PPAR.gamma.),
which is known to be activated by
.DELTA..sup.9-tetrahydrocannabinol.
Agonists of the PPAR.gamma. isoform improve insulin sensitivity and
are often used in the management of type 2 diabetes. Additionally,
PPAR.gamma. agonists have been shown to have positive
cardiovascular effects, which include in vitro evidence of
increased availability of nitric oxide (NO), and in vivo reductions
in blood pressure and attenuation of atherosclerosis.
Some of the beneficial effects of PPAR.gamma. ligands are brought
about by the anti-inflammatory actions of PPAR.gamma. activation,
including inhibition of pro-inflammatory cytokines, increasing
anti-inflammatory cytokines, and inhibition of inducible nitric
oxide synthase (iNOS) expression. It is therefore thought that the
use of PPAR.gamma. ligands might be a useful treatment option in
the pharmaceutical management of metabolic syndrome or diseases and
conditions associated with an increased risk of metabolic syndrome,
and may therefore counter the side-effects associated with the use
of atypical anti-psychotic medicaments.
In vitro vascular studies were carried out in rat isolated aortae
by wire myography. PPAR.gamma. activation was investigated using
reporter gene assays, a PPAR.gamma. competition-binding assay and
an adipogenesis assay.
Both THCV and CBD were dissolved in ethanol to a stock
concentration of 10 mM and further dilutions were made using
distilled water.
Results:
Time-Dependent Effects of CBD and THCV in the Aorta
CBD (10 .mu.M) caused significant time-dependent relaxation of the
rat aorta compared to vehicle control at all time-points over the
course of 2 h (2 h, vehicle 19.7.+-.2.4% cf CBD 69.7.+-.4.0%
relaxation, n=13, P<0.001. After 2 h, the residual relaxation
(the vasorelaxant effect of CBD minus the vasorelaxant effect of
vehicle and time) was 50.1.+-.3.3% relaxation.
CBD had no effect on basal tension over time (2 h, vehicle
-0.02.+-.0.01 g cf CBD -0.03.+-.0.01 g, n=7).
In pre-contracted aortae, THCV (10 .mu.M) had no effect on tone
until after 105 minutes, and after 120 min, vasorelaxation to THCV
was 28.7.+-.4.6% relaxation (n=10), compared to 15.1.+-.4.6%
(P<0.01) in control arteries.
In the presence of the PPAR.gamma. receptor antagonist GW9662 (1
.mu.M), the residual vasorelaxant effect of CBD was significantly
reduced after 1 h of incubation. The vasorelaxant effect of CBD was
similar in endothelium-denuded and control aortae. Similarly, in
the presence of the nitric oxide synthase inhibitor, L-NAME (300
.mu.M), the residual vasorelaxant effect of CBD was not different
to that observed in control conditions.
The CB.sub.1 receptor antagonist AM251 (1 .mu.M) did not
significantly affect the time-dependent vascular responses to CBD.
The CB.sub.2 receptor antagonist SR144528 (1 .mu.M) significantly
inhibited the residual vasorelaxant effects of CBD between 45 min
to 90 min. Pre-treating arteries with either PTX (200 ng ml.sup.-1,
2 h) or with capsaicin (10 .mu.M, 1 h) had no effect on the
vascular response to CBD over time.
When arteries were contracted with a high potassium buffer, there
was no difference in the vasorelaxant effect of CBD compared with
control. By contrast, in vessels where tone was induced with U46619
in calcium free buffer, the vasorelaxant effect of CBD was
significantly blunted compared with control.
The potency and maximal contractile response to the re-introduction
of calcium in calcium free, high potassium Krebs-Hensleit solution
was significantly reduced in a concentration-dependent manner the
presence of CBD from 1 .mu.M to 30 .mu.M. The calcium channel
blocker, verapamil, caused significant vasorelaxation of
pre-constricted vessels as CBD, although with a more rapid
onset.
Effects of Chronic Treatment of Rats with CBD on Vascular Responses
in Isolated Arteries
Animals were treated for 2 weeks with either vehicle or CBD, and
investigations of arterial function made.
In small resistance mesenteric vessels, the maximal contractile
responses to methoxamine were significantly lower in CBD-treated
animals than in vehicle-treated animals (R.sub.max 1.56.+-.0.13 g
vs CBD 2.20.+-.0.13 g increase tension, n=7, P<0.001). CBD
treatment caused an additional decrease in the potency of
methoxamine (pEC.sub.50 veh 5.94.+-.0.08 vs CBD 5.79.+-.0.10,
P<0.05).
The maximal response to methoxamine in the aorta was also
significantly higher in vehicle-treated animals (2.32.+-.0.20 g
increase tension, n=6) compared to CBD-treated animals
(1.63.+-.0.21 g increase tension, n=7, P<0.001).
Repeated treatment with CBD did not affect the vasorelaxant
responses to acetylcholine in small resistance mesenteric arteries.
However, in the aorta, CBD treatment significantly decreased the
potency of acetylcholine (pEC.sub.50 control 6.17.+-.0.31 vs
CBD-treated 5.37.+-.0.40, n=6, P<0.01).
Transcriptional Transactivation Assays
To determine whether CBD stimulates PPAR.gamma., transactivation
assays were performed in homologous cells transiently
overexpressing PPAR.gamma. and RXR.alpha. in combination with a
luciferase reporter gene (3.times.PPRE TK luc).
In these assays, the synthetic PPAR.gamma. agonist rosiglitazone
(10 .mu.M) significantly stimulated the transcriptional activity of
PPAR.gamma. compared to vehicle-treated cells transfected with all
DNA (148.+-.7 cf 319.+-.7 relative luciferase activity (per ng
ml.sup.-1 protein), P<0.01).
Likewise, CBD also significantly stimulated the transcriptional
activity of PPAR.gamma. compared to untreated-cells at 10 .mu.M
(305.+-.18 relative luciferase activity, P<0.01) and 20 .mu.M
(470.+-.37 relative luciferase activity, P<0.01) in a
concentration-dependent manner.
THCV had no effect on PPAR.gamma. transcriptional activity at any
concentration tested.
Induction of Adipocyte Differentiation
3T3L1 cells were cultured until confluent and then treated for 8
days with either CBD or rosiglitazone. Cells were fixed and stained
with Oil Red O to identify fat droplets, to the presence of which
indicates differentiation of fibroblasts into adipocytes. Untreated
cells showed some signs of differentiation, but the majority of
cells retained their spindle shape with little Oil Red O staining.
Rosiglitazone induced differentiation of 3T3 L1 cells to
adipocytes, as evidenced by large amounts of Oil Red O staining
indicating fat droplet accumulation within the cytoplasm. In the
presence of CBD, signs of fat droplet accumulation were apparent at
all concentrations tested in a concentration-dependent manner.
Conclusions
These data provide strong evidence that CBD is a PPAR.gamma.
agonist, and suggest a novel means by which the effects of CBD
could be brought about. In light of the emerging evidence that
PPAR.gamma. ligands have beneficial effects in type 2 diabetes, the
cardiovascular system and potentially in a wide variety of other
disorders including cancer, gastroinflammatory disorders and many
skin diseases, these data provide evidence that cannabinoids could
be useful in, amongst other things, the prevention of the metabolic
symptoms associated with the use of anti-psychotic drugs.
Example 4
Methodology
Conditioned avoidance behavior was assessed using two automated
shuttle-boxes (46 W.times.19.5 D.times.20 H cm, BIO MEDICA, Ltd)
each placed in a sound-attenuated chamber. Each trial consisted of
a 10 s warning tone (105 dB tone) as a conditioned stimulus (CS)
followed by 10 s foot shock (1 mA) as an unconditioned stimulus
(US) and 15-75 (mean; 45) s inter-trial interval. The US was
terminated when the animal jumped over the hurdle from one
compartment to the other or after a cut-off time of 10 s. Each rat
was placed in one of the compartments of the shuttle box and
allowed to freely explore it for 1 min before the first trial.
During the training session, three kinds of responses were
recorded: if crossing occurred in response to CS alone, a CAR was
recorded; if crossing occurred during the period in which US was
presented, an escape response was recorded; if the rats failed to
react, an escape failure (EF) was recorded. Animals Species/Strain:
rat/Wistar Supplier: Japan SLC, Inc Sex: male Age (at time of
beginning of training session): 6 weeks
When the animal completed successfully an over 75% avoidance rate
(15 CAR/20 trials) for 3 consecutive training sessions, it was
defined as well-trained CAR and was used for evaluating the effects
of compounds the next day.
The dosing regime for CBD is as illustrated in FIG. 1 and for THCV
is illustrated in FIG. 2. (Vehicle 1: 5% Arabic gum, Vehicle 2:
EtOH:chremohor:saline=1:1:18)
CBD and THCV were synthesized and used in this example.
Results
Example 4
i) Effect of Aripoprazole APZ (7.5 mg/kg po) and THCV (60 mg/kg ip)
at Sub Effective Dose Levels (when Used Alone)
The results are illustrated in FIG. 3 which is a bar chart showing
the effect of: Vehicle 1 and vehicle 2; APZ and vehicle 2 THCV and
vehicle 1; and APZ and THCV.
Surprisingly a combination effect was detected.
*p<0.05, **p<0.01 (vs combination group) by 2-tailed Dunnett
test, n=9-10
Vehicle 1: 5% Arabic gum
Vehicle 2: EtOH:chremohor:saline=1:1:18
ii) Effect of Aripoprazole APZ (15 mg/kg po) and THCV (60 mg/kg ip)
at Effective Dose Levels (when APZ Used Alone)
The results are illustrated in FIG. 4 which is a bar chart showing
the effect of: Vehicle 1 and vehicle 2; APZ and vehicle 2 THCV and
vehicle 1; and APZ and THCV concentration.
Again a combination effect was observed at these doses on CAR.
*p<0.05, **p<0.01 (vs combination group) by 2-tailed Dunnett
test, n=12
#p<0.05 (vs Vehiclel+2 group) by 2-tailed Dunnett test
Vehicle 1: 5% Arabic gum,
Vehicle 2: EtOH:chremohor:saline=1:1:18
Example 5
Effect of CBD and THCV on Catalepsy (5a) and Ptosis (5b)
Methodology
Animals
Species/Strain: rat/Wistar
Supplier: Japan SLC, Inc
Sex: male
Age (at the test day): 6-7 weeks
Animals were subjected to a protocol as illustrated in FIG. 5.
Vehicle 1: 5% Arabic gum,
Vehicle 2: EtOH:chremohor:saline=1:1:18
Rats were made to fast from 6 PM on the day before the experiment
until sacrifice. Rats were weighed and orally (PO) administered
aripiprazole. Then, rats were intraperitoneally (IP) injected
cannabinoids (CBD and THCV) 1 hour after administration of
aripiprazole. Catalepsy and ptosis were observed at 2, 4, 6 and 8
hours after the administration of aripiprazole. For measurement of
catalepsy, the observations were performed three times at each
observation time point. The animals were forced to hang with their
right forepaw on the upper edge of a steel can (diameter: 6 cm,
height: 10 cm). When the animals remained in the unnatural vertical
position for 30 seconds or longer, they were judged to be positive
responders for catalepsy.
The measurement of ptosis was performed as follows. Each animal was
individually taken from the home cage and put on the experimenter's
hand to observe the eyes. The ptosis score was determined for both
eyes as described below, and the scores for the two eyes were added
to obtain the total score (maximum score, 8) 0: Normal 1: Mild
ptosis (upper eyelid covered 1/4 of the eye) 2: Moderate ptosis
(upper eyelid covered 1/2 of the eye) 3: Severe ptosis (upper
eyelid covered 3/4 of the eye) 4: Complete ptosis (upper eyelid
covered the entire eye)
Results
Example 5a
The results at different doses are shown graphically in FIGS. 6a/6b
(APZ/CBD) and FIGS. 6a/6c (APZ/THCV).
By comparison of FIG. 6a with FIG. 6b it is apparent that CBD (120
mg/kg, ip) significantly decreased Aripiprazole-induced catalepsy
in rats (total, p=0.0286; 8 hr, p=0.0339, by generalized estimating
equations). i.e. a combination effect was detected.
n=8,
Vehicle 1: 5% Arabic gum, Vehicle 2:
EtOH:chremohor:saline=1:1:18
Similarly, by comparison of FIG. 6a with FIG. 6c it is apparent
that THCV (60 mg/kg, ip) significantly decreased
Aripiprazole-induced catalepsy in rats (total, p=0.0073; 8 hr,
p=0.0060, by generalized estimating equations). i.e. a combination
effect was detected.
n=8,
Vehicle 1: 5% Arabic gum, Vehicle 2:
EtOH:chremohor:saline=1:1:18
CBD and THCV were synthesized and used in this example.
Example 5b
The results are again shown graphically in FIGS. 7 (CBD) and 8
(THCV).
From FIG. 7 it is apparent that CBD (120 mg/kg, ip) significantly
decreased Aripiprazole-induced ptosis in rats (Drug (CBD),
p<0.01; Interaction, p<0.01, by 2-way ANOVA). i.e. a
combination effect was detected.
**p<0.01 by Wilcoxon Rank Sum test with Bonferroni's correction,
n=8,
Vehicle 1: 5% Arabic gum,
Vehicle 2: EtOH:chremohor:saline=1:1:18
Similarly from FIG. 8, it is apparent that THCV (60 mg/kg, ip)
significantly decreased aripiprazole-induced ptosis in rats (Drug
(THCV), p<0.01; Interaction, p<0.01, by 2-way ANOVA). i.e. a
combination effect was detected.
*p<0.05 by Wilcoxon Rank Sum test with Bonferroni's correction,
n=8,
Vehicle 1: 5% Arabic gum,
Vehicle 2: EtOH:chremohor:saline=1:1:18
CBD and THCV were synthesized and used in this example.
These examples, together with previously reported evidence,
demonstrate how the use of a number of different phyto-cannabinoids
in combination with anti-psychotic medicaments might be a more
beneficial treatment than the use of the anti-psychotic medication
alone as they may enable the reduction or removal of the
undesirable side effects of the anti-psychotic drugs and may
further provide additional anti-psychotic effects.
* * * * *